Prof Karim Fizazi – Department of Cancer Medicine, Institut Gustave Roussy, France
Prof Stephane Oudard – Hopital Europeen Georges Pompidou, Paris, France
Dr Bertrand Tombal – Université catholique de Louvain, Ottignies-Louvain-la-Neuve, Belgium
Prof Maria De Santis – Warwick Medical School Cancer Research, University of Warwick, UK
KF: I’m Karim Fizazi, medical oncologist at Gustave Roussy in Villejuif, France and I’m here in Madrid during this ESMO 2017 meeting for this ecancer event. Today we will speak about prostate cancer and mostly, of course, what was presented here at the congress. I’m glad to have a very nice faculty panel together with me including Professor Stephane Oudard from Paris, Georges Pompidou. We have also Professor Bertrand Tombal from Bruxelles, a urologist and also Professor Maria De Santis from the UK University of Warwick, medical oncologist as Stephane. Most of what we are going to discuss today is going to be about prostate cancer and I have to say it’s going to be mostly about metastatic prostate cancer. This is because we had new data recently during the congress but also in the last two or three years and all the patterns of treatment are really evolving rapidly. So, Stephane, just to get started, regarding the castration sensitive metastatic situation it’s fair to say that there are two standards of care that are emerging on top of classical ADT – docetaxel and abiraterone. A big question for all our colleagues soon if abiraterone is approved in this indication will be which one should they choose. Here at ESMO we had some data presented by the STAMPEDE group comparing directly the two treatments. Can you please elaborate on that?
SO: Yes, [?? 1:47] firstly presented data about the different randomised clinical trials from the STAMPEDE studies looking at the different situations, ADT with different drugs, and she found out that in fact the two drugs which are the best in combination with ADT is ADT with docetaxel or ADT plus abiraterone. She found by doing a network analysis that in fact the best one, the best combination, is ADT plus abiraterone leading to a 93% probability of good outcome. She said that the second choices would be to look at ADT plus docetaxel leading to a 43% probability of good outcome. But she made this study not on the individual patient population and characteristics. I think there are two major problems for this analysis because she did not take into account the tumour burden of the different clinical trials and, as you know, in the CHAARTED trial and in the STAMPEDE trial we have a much higher tumour burden than in the GETUG-15 trial, for instance, so it’s difficult to compare. In addition to that she didn’t look at secondary treatments at relapse so it’s difficult just to give an answer about which drug is the best, in fact. On top of that the first day Matt Sydes looked at the retrofit between abiraterone plus ADT or ADT plus docetaxel and he wanted to make a clear analysis going from failure free survival to metastatic free survival to OS. He found that maybe there is a trend towards better efficacy if you look at ADT plus abi in terms of metastatic free survival but if you look at OS data he found that there is no difference at all in fact. So I think that we can’t say anything, we cannot recommend anything to our clinicians and to our patients about which treatment is the best so far.
KF: Alright, so it’s probably fair to say that we have plus or minus two standards of care at the moment. Bertrand, there were data presented at the congress regarding the LATITUDE trial and the patient reported outcomes. I think that’s very important on top of duration of life and extension of the duration of life, can you tell us more about it?
BT: Indeed it was probably one of the most important missing pieces of the puzzle because, as Stephane just explained, when you compare docetaxel to abiraterone you see that because of its mode of action it’s delaying progression extremely efficiently. But the question is what life do we offer to these patients? After your presentation at ASCO there was a lot of what I would even call bashing about the fact that there are corticoids, that they are going to have a lot of toxicity, that it’s going to deteriorate their quality of life. So there were a lot of questions and actually Kim Chi presented the patient reported outcomes, so basically standard assessment of quality of life, and made two observations. The first one is that, as we know, urologists from all trials, patients on ADT with high volume cancer deteriorate extremely rapidly. In contrast to what is always said, ADT alone doesn’t have a major effect on quality of life or if it has one it is very, very short. Although it’s difficult to distinguish from cancer progression the benefit is not huge and what you see is that when you combine to abiraterone you have a major and sustained benefit in quality of life. Once again the time quality of life deteriorates is difficult to differentiate from clinical progression but it should reassure. All that said, when you had a corticoid actually you have a negative impact on quality of life, we don’t see any of this. If you take an instrument, which for us Europeans is extremely important, which is the EQ-5D because this is what all health economists are going to use to justify that expensive money, when you look at the health status impact on EQ-5D it is really dramatic so that would help.
KF: Basically it’s fair to say that abiraterone not only postpones death in this setting but also improves pain, fatigue and quality of life which is great.
BT: A major impact, yes.
KF: Now, at the end of the day should we, or at least in the future, should we keep using two treatments, ADT docetaxel or ADT abiraterone, or should we combine everything all together like it is currently tested in the PEACE-1 trial or in the ARASENS trial. Can you elaborate on ARASENS for example?
BT: Once again you refer to Stephane’s presentation, he showed a nice graph of John Isaacs showing that actually progression is a mix of adaptation and clonal progressions. So it makes sense from the physiological standpoint to combine the two treatments but this needs to be tested in clinical trials. There are trials like PEACE-1 or ENZAMET, for instance, where there have been, or ARCHES, the enzalutamide trial, that will give the possibility of adding docetaxel or not. So it may still not fully answer the question, that’s why ARASENS was developed. The idea that we’re going to design a trial where everybody will receive docetaxel so the entry point is not ADT anymore, it is ADT plus docetaxel. So you may argue that you’re going to select a population of patients that are fit for docetaxel but that is the population. On top of that we are adding a new AR pathway inhibitor which in this case is ODM-201 or darolutamide. So that’s what we expect to see in this triple combination – the benefit of adding an AR pathway inhibitor on docetaxel.
KF: I think these questions are really key because it really has the potential to even increase again the duration and quality of life. Maria, in STAMPEDE actually not all patients are metastatic so we do have data of abiraterone, or ADT plus or minus abiraterone, in patients with non-metastatic disease and some data were presented here at ESMO. Can you summarise that to us?
MDS: Yes, but let me start with praising the trial design of STAMPEDE because it is really different from the other randomised controlled trials that only included the M1 population. In STAMPEDE about 40% of patients had no metastatic disease but high risk features that made them eligible for the trial. In those patients the trial protocol with regards to the abiraterone arm, for example, was different from the metastatic arm because the patients included with M0 disease received abiraterone for only two years so only limited treatment burden compared to the metastatic patient population. In addition those patients in the STAMPEDE trial which is a multi-arm and multi-stage design, in this trial also patients were randomised to receive radiotherapy treatment of the local disease. So we have very different aspects looked at in this randomised controlled trial. So as for the M0 population, for the endpoint failure free survival, there was a huge benefit with regards to the hazard ratio in favour of treating the patients with abiraterone and not only with standard of care, so adding treatment in those patients for the two years. This was also significantly positive for the metastatic failure free survival. For the overall survival we assume a benefit but still it is maybe early days and maybe those patients will have so few events that we will never see the true or overall survival benefit because they might even be cured.
KF: So based on this data, and you work in the UK, do you think we have a new emerging standard of care for these men or should we wait for more data, longer follow-up, time to metastasis and, as you said, maybe overall survival in the long term before using abiraterone in high risk localised disease? What do you think?
MDS: This is difficult to answer because there is no NICE approval so far for the use of abiraterone in that setting, neither for the metastatic patients nor for the M0 patients. But from the medical oncologist’s point of view and seeing all those patients and seeing the great results and being assured that the quality of life and the treatment burden is actually not as bad as was anticipated, it would make sense, definitely sense, to treat those patients early on and maybe a few of the patients really provide very long term survival without progression. These endpoints are really important for the patients – not progressing with PSA, not progressing to metastatic disease and not being in need of additional treatment.
KF: I guess we need probably still a longer follow-up to use that as a standard of care but the signal is obviously very, very good and very strong at this moment. Stephane, in prostate cancer we do have a very specific situation in the middle of localised disease and metastatic disease which does not necessarily exist in other cancers. It’s really the rising PSA setting where you don’t see where the disease is located but you know it’s progressing. You have been able to conduct a randomised trial testing docetaxel in this setting on top of ADT. You just presented the data here at ESMO, can you summarise that for us please?
SO: When you speak about rising PSA, the first rise in PSA, in fact the tumour burden is really low. You are dealing with circulating tumour cells and maybe micrometastases that we can see at the imaging so far. So it was a study which began in 2003, so a long time ago, and the objective was to see whether or not we can increase the PSA PFS with ADT plus docetaxel compared to ADT alone. We entered 250 patients in this study and at the end in fact there is a trend towards a better efficacy in terms of PSA PFS but what is the meaning of PSA PFS in this setting, it was a long time ago, in favour of ADT plus docetaxel regarding all the patient characteristics. But the p-value was not significant and when you look at the rPFS on the rise there is no difference so far. So maybe at this stage of this disease maybe if you use hormonal therapies enough at least it doesn’t add anything on top of ADT. But in this patient population we have a very good outcome in terms of ten year overall survival – 70% of the patients were free of disease at this stage. So the question is do we need to treat those patients with ADT. Going back to the opposite side, saying that maybe for some patients we don’t need to do anything.
KF: Just follow them. Yes, and probably this is also based on PSA doubling time, as we all know, to try to better select all the patients for intervention versus surveillance. I guess one striking thing that is emerging for prostate cancer patients is the DNA repair question or DNA repair defect question. So a subpopulation of all the patients had either germline or somatic DNA repair gene abnormalities that make their cancer different and also that make potentially their families different. So, Bertrand, can you summarise where we currently stand and what we’ve learned here at ESMO regarding this?
BT: In a nutshell we have two information. The first one is that even in high risk localised disease you can spot some of these patients, as we know from [?? 14:38] UK trial. We have a better idea of the usual suspects: BRCA1, BRCA2, ATM, Chk2 but there are many other DNA repair mutations involved. The patients who have these mutations clearly have a worse prognosis. Is it enough to change the treatment today? The answer is no, it was clear from the Spanish trial, they still respond very well to ADT, surgery, radiotherapy, enzalutamide, abiraterone. So comes the question when should we look at it? Outside a clear family history, but that’s where we have to teach medical oncologists and urologists to do a proper medical history, we are waiting from guidelines from NCCN to see exactly what should we check. Then the second information, when the patient is progressing on enza, on abi, after docetaxel, we must get used to checking for somatic mutations because when patients have DNA repair mutation there is and there will be therapeutic opportunity. Not only PARP inhibitors, it’s very hyped, but also platinum compounds. So this is where we are today but it’s moving very, very rapidly and we need to learn about this and we need to learn more about doing proper genetic histories of our patients.
KF: Absolutely. There are actually quite large programmes starting or already started with PARP inhibitors and, as you said, also with some platinum trials ongoing. Here at ESMO, Maria, we had some presentations regarding the large TRITON programme with rucaparib. Can you tell us what that is?
MDS: The TRITON programme follows that knowledge that Bertrand was just explaining. We have seen preliminary evidence that patients with DNA repair deficiencies respond better to PARP inhibitors than those who have not. This was linked to BRCA1/2 and to ATM aberrations but there are also other genes that might make the patient more eligible for this kind of treatment with PARP inhibitors. There are several PARP inhibitors out there and the TRITON programme uses rucaparib. The TRITON-2 is a phase II trial, it looks at the usual BRCA1/2, ATM and a twelve panel gene with other aberrations, selects the patients and treats the patients with the endpoint response rate. So RECIST response or PSA response, just a signal finding study, I would interpret it. The other larger programme is a randomised phase III trial, again using rucaparib and this is a trial in patients that progressed on AR inhibitor treatment like abiraterone or enzalutamide. These patients should not have been pre-treated with docetaxel, those patients would be excluded. The patients get randomised to receive either rucaparib in this situation or investigator’s choice of treatment with abiraterone, enzalutamide or chemotherapy with docetaxel. The endpoint here is radiographic progression free survival which makes sense because there is a good link, and this has been shown and published recently, a good link between radiographic progression free survival and overall survival. I think we need a more immediate endpoint here.
KF: Absolutely. TRITON is one of the programmes, the large programmes, that we have at the moment with PARP inhibition. There are others, which is just great for all the patients because it provides them an opportunity to receive one of these agents. We don’t really know whether one is better than the other one, to be honest, regarding the PARP inhibitors but really having several programmes running in parallel provides an opportunity for patients to get at least one, which is probably very important to them. So I think we’ve covered plus or minus the big news that we had here at ESMO 2017 regarding prostate cancer. I would like to thank you for this conversation, it was fun doing that together, and really we see major progress, congress after congress, in prostate cancer in the last years. It’s really fantastic so I’m glad we’re here to summarise that. Finally I would just like to thank you for attending this ecancer event. Thank you very much.